uPAR: An Essential Factor for Tumor Development

Abstract

Tumorigenesis is closely related to the loss of control of many genes. Urokinase-type plasminogen activator receptor (uPAR), a glycolipid-anchored protein on the cell surface, is controlled by many factors in tumorigenesis and is expressed in many tumor tissues. In this review, we summarize the regulatory effects of the uPAR signaling pathway on processes and factors related to tumor progression, such as tumor cell proliferation, adhesion, metastasis, glycolysis, tumor microenvironment and angiogenesis. Overall, the evidence accumulated to date suggests that uPAR induction by tumor progression may be one of the most important factors affecting therapeutic efficacy. An improved understanding of the interactions between uPAR and its coreceptors in cancer will provide critical biomolecular information that may help to better predict the disease course and response to therapy.

Keywords: adhesion; cancer therapy; metastasis; proliferation; tumorigenesis; uPAR.

Figure 1

Two dimensional (2D) and three dimensional (3D) structures of uPAR. (A) uPAR encodes a protein of 335 amino acids comprising 22 amino acids (secreted signal peptides) at the N-terminus and 30 amino acids at the C-terminus. uPAR consists of three domains ranging in size from 81 to 87 amino acids, namely, D1, D2 and D3, which are connected by short linker regions. (B) The 3D structure of uPAR, with domains colored as in part(Protein Data Bank identifier 3BT2). (C) PAI-1 and PAI-2 exhibit inhibitory action on the uPA/uPAR system. Phospholipase C cleaves and releases uPAR from the cell membrane surface to suPAR, and uPAR cleavage results in hydrolysis of the specific SMB-binding site between D1 and D2 in the uPAR structure. Consequently, there are three different structural forms of suPAR: the complete D1+D2+D3 structure, the D2+D3 structure and the free D1 fragment.

Figure 2

The function of tumor cells is regulated by uPAR. uPAR regulates the proliferation, metastasis, adhesion, glycolysis and angiogenesis of tumor cells through cell signaling, and plays an important role in the tumor microenvironment.

Figure 3

Function and regulation of uPAR in tumor cell proliferation. (A) The interaction of the uPA-uPAR-α5β1 integrin complex with EGFR enables the Src homology 3 domain (SH3) in the intracellular domain of integrin α5β1; this leads to the activation of FAK, which results in Ras activation and MAPK expression. The uPA-uPAR-α5β1 integrin complex can bind to GPCR to transmit signals and promote tumor cell proliferation. SPRY1 can interact with uPAR and promote its lysosomal-mediated degradation, resulting in inhibition of the activation of the FAK and ERK pathways, which suppresses the tumor proliferation induced by uPAR. (B) D1 and D2 of uPAR are crucial for EGFR activation, which is as effective as EGF in promoting MAPK and FAK, and cell proliferation.

Figure 4

Function and regulation of uPAR in tumor cell adhesion. (A) Two modes of uPAR signal regulation. In canonical signaling, integrins engage the specific ligands in the ECM. In non-canonical integrin, uPAR-mediated cell adhesion, through the plasma membrane, transmits a mechanical stimulus to the integrin that signals independently of ECM binding. (B) The downstream signaling cascade of uPAR/CD151/α3β1 integrin shows that phosphorylation of FAK, Src and paxillin is reduced with knockdown of cathepsin B, uPAR, and CD151. (C) Other cellular proteins regulate tumor cell adhesion through uPAR.

Figure 5

The regulatory network of uPAR through the ECM, integrin, TGF-β and noncoding RNA in tumor migration. (A) uPA binds to uPAR, and the inactive pro-uPA precursor is transformed into active uPA. Then uPA cleaves inactive plasminogen into active plasmin, which further cleaves and activates downstream MMPs. The fibrinolytic proteases and MMPs formed after activation will hydrolyze ECM and release active EGF, which promotes tumor invasion and metastasis. (B) Integrin and uPA/uPAR form the structure of the uPA-uPAR integrin complex signal, and drive the activation of GTPase Rac actin assembly, the cell wall of actin protrusions extends forward, and pericytes outside the cytoplasmic membrane protein (pericyclic protein) decomposition are eliminated outside the ECM barrier membrane. (C) TGF-β1 induces epithelial-mesenchymal transition (EMT) with an associated upregulation of uPA, uPAR, cathepsin B and MMP-9. TGF-β activates the Ras/MKK4/JNK1 signaling cascade, leading to the induction of AP-1 activity, which promotes cell migration. (D) MicroRNAs regulate uPAR-induced ECM formation and protein degradation, which play an important role in cancer cell metastasis.

Figure 6

The regulatory network of uPAR in glycolysis. Hypoxia can enhance the expression of endogenous uPAR in a HIF-1α dependent manner. Inhibition of uPAR with siRNA or uncoupling of uPAR from integrin-linked tyrosine receptors (IL-TKRs) inhibits the PI3K/AKT/mTOR/HIF-1α signaling pathway, resulting in impaired glucose uptake and a reduction in PKM2 and other glycolytic enzymes, thereby controlling the metabolism of cancer cells.

Figure 7

CAR-T cells targeting uPAR can be utilized for cells. uPAR is identified as a common upregulated marker in senescent cells in three different models: therapy-induced senescence (TIS), oncogene-induced senescence (OIS), and replication-induced senescence (RIS). Senolytic CAR T cells were generated by introducing anti-mouse uPAR scFv linked to human CD28 costimulatory and CD3ζ signaling domains, resulting in T cell activation and degranulation.